Involvement of JNK/p73/NOXA in vitamin E analog‐induced apoptosis of human breast cancer cells

Microarray analyses of human MDA‐MB‐435 breast cancer cells treated with vitamin E analog 2,5,7,8‐tetramethyl‐2R‐(4R,8R,12‐trimethyltridecyl) chroman‐6‐yloxy acetic acid (α‐TEA) showed over 400 genes to be modulated. Thirty‐four genes deemed of interest based on potential involvement in anticancer activities of α‐TEA fell into six categories: apoptosis related, signal transduction, cell cycle related, cell adhesion and motility, transcriptional regulators, and membrane traffic related. The gene (PMAIP1) for NOXA was studied further. NOXA mRNA and protein levels were elevated in a time and dose‐dependent fashion following α‐TEA treatment. Functional knockdowns using small interfering RNA (siRNA) showed NOXA to contribute to α‐TEA‐induced apoptosis. A correlation between α‐TEA's ability to upregulate NOXA and induce apoptosis was seen among several human breast cancer cell lines. Efforts to identify upstream regulators of NOXA in α‐TEA‐induced apoptosis identified the necessity of both c‐Jun N‐terminal kinase (JNK) activation and p73 expression. Additionally, protein levels of full length p73 were decreased by JNK siRNA treatment, suggesting that the signal transduction module of JNK‐p73‐NOXA is involved in α‐TEA induced apoptosis of human breast cancer cells. Taken together, these findings suggest a role for JNK activation in mediating full length p73 expression and add to our understanding of the mechanisms of anticancer actions of α‐TEA, a potential chemotherapeutic agent. © 2007 Wiley‐Liss, Inc.

[1]  Karla A. Lawson,et al.  In vitro and in vivo evaluation of anticancer actions of natural and synthetic vitamin E forms. , 2008, Molecular nutrition & food research.

[2]  A. Whitmarsh,et al.  Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase. , 2007, The Biochemical journal.

[3]  Chad J. Creighton,et al.  MDA-MB-435 cells are derived from M14 Melanoma cells––a loss for breast cancer, but a boon for melanoma research , 2007, Breast Cancer Research and Treatment.

[4]  J. Armstrong,et al.  Role of Noxa in p53-independent fenretinide-induced apoptosis of neuroectodermal tumours , 2007, Apoptosis.

[5]  T. Hahn,et al.  Dietary administration of the proapoptotic vitamin E analogue alpha-tocopheryloxyacetic acid inhibits metastatic murine breast cancer. , 2006, Cancer research.

[6]  B. G. Sanders,et al.  α-TEA inhibits survival and enhances death pathways in cisplatin sensitive and resistant human ovarian cancer cells , 2006, Apoptosis.

[7]  Jian Gu,et al.  PI3K signaling and miRNA expression during the response of quiescent human fibroblasts to distinct proliferative stimuli , 2006, Genome Biology.

[8]  K. Watabe,et al.  Vitamin E succinate suppresses prostate tumor growth by inducing apoptosis , 2006, International journal of cancer.

[9]  N. Stott,et al.  MG132 induced apoptosis is associated with p53-independent induction of pro-apoptotic Noxa and transcriptional activity of β-catenin , 2006, Apoptosis.

[10]  L. Bundy,et al.  C/EBPbeta-2 confers EGF-independent growth and disrupts the normal acinar architecture of human mammary epithelial cells , 2005, Molecular Cancer.

[11]  S. Willis,et al.  Life in the balance: how BH3-only proteins induce apoptosis. , 2005, Current opinion in cell biology.

[12]  M. Hendrix,et al.  Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. , 2005, Cancer research.

[13]  G. Melino,et al.  E1A Activates Transcription of p73 and Noxa to Induce Apoptosis* , 2005, Journal of Biological Chemistry.

[14]  L. Hawthorn,et al.  Up-regulation of c-Jun-NH2-kinase pathway contributes to the induction of mitochondria-mediated apoptosis by alpha-tocopheryl succinate in human prostate cancer cells. , 2005, Molecular cancer therapeutics.

[15]  Yue Wu,et al.  Cellular and molecular effects of alpha-tocopheryloxybutyrate: lessons for the design of vitamin E analog for cancer prevention. , 2004, Anticancer research.

[16]  Karla A. Lawson,et al.  Comparison of Vitamin E Derivatives α-TEA and VES in Reduction of Mouse Mammary Tumor Burden and Metastasis , 2004, Experimental biology and medicine.

[17]  Karla A. Lawson,et al.  Vitamin E Analog α-TEA and Celecoxib Alone and Together Reduce Human MDA-MB-435-FL-GFP Breast Cancer Burden and Metastasis in Nude Mice , 2004, Breast Cancer Research and Treatment.

[18]  M. Hendrix,et al.  p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas. , 2004, Molecular cancer therapeutics.

[19]  Karla A. Lawson,et al.  Differential Response of Human Ovarian Cancer Cells to Induction of Apoptosis by Vitamin E Succinate and Vitamin E Analogue, α-TEA , 2004, Cancer Research.

[20]  Karla A. Lawson,et al.  Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis , 2004, Cancer Chemotherapy and Pharmacology.

[21]  V. Iyer,et al.  Genome-Wide Analysis of the Biology of Stress Responses through Heat Shock Transcription Factor , 2004, Molecular and Cellular Biology.

[22]  Gordon B Mills,et al.  Lineage Infidelity of MDA-MB-435 Cells , 2004, Cancer Research.

[23]  X. Chen,et al.  The common and distinct target genes of the p53 family transcription factors , 2004, Cellular and Molecular Life Sciences CMLS.

[24]  Rachel J Parsons,et al.  Pro-apoptotic Mechanisms of Action of a Novel Vitamin E Analog (α-TEA) and a Naturally Occurring Form of Vitamin E (δ-Tocotrienol) in MDA-MB-435 Human Breast Cancer Cells , 2004 .

[25]  S. Akira,et al.  Integral role of Noxa in p53-mediated apoptotic response. , 2003, Genes & development.

[26]  Gavin Sherlock,et al.  The Longhorn Array Database (LAD): An Open-Source, MIAME compliant implementation of the Stanford Microarray Database (SMD) , 2003, BMC Bioinformatics.

[27]  Karla A. Lawson,et al.  Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastasis. , 2003, Molecular cancer therapeutics.

[28]  B. Gusterson,et al.  p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. , 2003, Cancer cell.

[29]  W. Hahn,et al.  Chemosensitivity linked to p73 function. , 2003, Cancer cell.

[30]  L. Fan,et al.  Potential role of p53 on metallothionein induction in human epithelial breast cancer cells , 2002, British Journal of Cancer.

[31]  W. Yu,et al.  RRR-alpha-tocopheryl succinate induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo differentiation. , 2001, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[32]  F. Hantash,et al.  Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells. , 2001, Cancer research.

[33]  R. Baxter,et al.  Growth Inhibition by Insulin-like Growth Factor-binding Protein-3 in T47D Breast Cancer Cells Requires Transforming Growth Factor-β (TGF-β) and the Type II TGF-β Receptor* , 2000, The Journal of Biological Chemistry.

[34]  T. Taniguchi,et al.  Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. , 2000, Science.

[35]  W. Yu,et al.  Vitamin E succinate (VES) induces Fas sensitivity in human breast cancer cells: role for Mr 43,000 Fas in VES-triggered apoptosis. , 1999, Cancer research.

[36]  P. Brown,et al.  RRR‐α‐tocopheryl succinate induction of prolonged activation of c‐jun amino‐terminal kinase and c‐jun during induction of apoptosis in human MDA‐MB‐435 breast cancer cells , 1998 .

[37]  S. Fuqua,et al.  Differential expression of wild-type and variant ER mRNAs by stocks of MCF-7 breast cancer cells may account for differences in estrogen responsiveness. , 1995, Biochemical and biophysical research communications.

[38]  J. Price,et al.  Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. , 1990, Cancer research.

[39]  B. G. Sanders,et al.  alpha-TEA inhibits survival and enhances death pathways in cisplatin sensitive and resistant human ovarian cancer cells. , 2006, Apoptosis : an international journal on programmed cell death.

[40]  Rachel J Parsons,et al.  Pro-apoptotic mechanisms of action of a novel vitamin E analog (alpha-TEA) and a naturally occurring form of vitamin E (delta-tocotrienol) in MDA-MB-435 human breast cancer cells. , 2004, Nutrition and cancer.

[41]  K. Mrózek,et al.  Human papillomavirus type 16 E6 inactivation of p53 in normal human mammary epithelial cells promotes tamoxifen-mediated apoptosis. , 2001, Cancer research.

[42]  R. Baxter,et al.  Growth inhibition by insulin-like growth factor-binding protein-3 in T47D breast cancer cells requires transforming growth factor-beta (TGF-beta ) and the type II TGF-beta receptor. , 2000, The Journal of biological chemistry.

[43]  C. Hoefnagel.  Neuro-ectodermal tumours , 1998 .